Project Summary Hypertension is the leading cause of death and disability-adjusted life years worldwide. Despite current therapies blood pressure remains uncontrolled in approximately 50% of individuals with hypertension, and even with adequate control of BP an elevated risk of cardiovascular events remains. Hence, there is a major unmet need for new therapeutic options for hypertension. Emerging evidence suggests an important role for the immune system in the pathogenesis of hypertension. An immune cell subset termed regulatory T cells (Tregs) is an attractive therapeutic target as it plays a suppressive role to limit inflammation. However, recent evidence suggests that Tregs can play pathogenic roles in heart failure and lung fibrosis through inhibiting angiogenesis and promoting fibrosis. Novel evidence provided with this application suggests that a subpopulation of Tregs expressing C-C motif chemokine receptor 10 (CCR10) is selectively decreased in the circulation of hypertensive humans and mice and is increased in the skin of mice with hypertension. Given recent evidence for an important role for skin microvascular rarefaction (defined as loss of microvessels) in hypertension, these results suggest a novel link between CCR10+ Tregs, skin microvessels, and hypertension development. To understand a mechanism for these effects, we evaluated the effects of increased endothelial cell stretch, as occurs with elevated blood pressure, on immune cells and found that CCR10+ Tregs are selectively increased with enhanced endothelial stretch. Thus, studies in this application will test the hypothesis that increased endothelial cell stretch augments CCR10 expression in Tregs and promotes CCR10+ Treg recruitment to the skin to enhance microvascular rarefaction and hypertension development. This hypothesis will be tested with the following specific aims: 1) to test the hypothesis that increased EC stretch enhances CCR10 expression in Tregs via tumor necrosis factor alpha and to determine whether resultant CCR10+ Tregs transmigrate and inhibit angiogenesis in response to CCR10 agonism by C-C motif chemokine ligand 27 (CCL27) in vitro, 2) to determine whether CCR10+ Tregs promote skin microvascular rarefaction leading to elevated blood pressure in salt and angiotensin II-induced hypertensive mouse models in vivo, and 3) to test whether CCR10 and its skin-specific ligand CCL27 promote hypertension in humans using a genetic approach of Mendelian randomization. Execution of the outlined experiments will provide a platform for the applicant to gain further understanding and skills related to the study of regulatory T cells and skin microvasculature as well as human genetic approaches such as Mendelian randomization. This work will be performed at Vanderbilt University Medical Center which has outstanding resources and mentorship to enable successful attainment of the career goals of the applicant, namely to become an independent physician scientist caring for patients with hypertension and studying the role of regulatory T cells in development of this disease to help develop new therapeutic options for treatment.